The importance of NK cells in controlling viral and bacterial infections, and possibly cancer, is increasingly recognized. Only recently has there been progress in understanding the basis of their specificity. One important component involves recognition of MHC or MHC-like class I molecules. NK cells express inhibitory class I specific receptors that can prevent NK cell activation, cytokine production and target cell lysis. A complete understanding of these receptors and their biological specificity is critical to understanding the function of NK cells in infections and cancer. The investigator proposes to continue efforts to elucidate the function, specificity, repertoire and functional activity of NK class I-specific inhibitory receptors in the mouse, including the Ly49 and CD94/NKG2 receptors, and to examine their role in murine cytomegalovirus (MCMV) infections. The first aim (1) is to complete the characterization of Ly49 receptor specificity with the use of new mAbs against all the of the Ly49 receptors, and binding studies of Ly49 receptors to class I molecules. The second aim (2) is to clone murine CD94/NKG2 receptors, produce mAbs against them, examine their specificity for class I molecules, and produce transgenic and knockout mice for further functional analyses. The third aim (3) is to use anti-Ly49 and anti- CD94/NKG2 mAbs and staining and functional studies to elucidate the nature of the NK cell inhibitory receptor repertoire for self class I molecules. The fourth aim (4) is to determine the role of the MCMV m144 class I homolog protein in preventing NK cell responses and the role of corresponding NK cell receptors in regulating NK immunity to MCMV infection.